Samuel J. Gatley

Loss of Dopamine Transporters in Methamphetamine Abusers Recovers with Protracted Abstinence

Methamphetamine is a popular drug of abuse that is neurotoxic to dopamine (DA) terminals when administered to laboratory animals. Studies in methamphetamine abusers have also documented significant loss of DA transporters (used as markers of the DA terminal) that are associated with slower motor function and decreased memory. The extent to which the loss of DA transporters predisposes methamphetamine abusers to neurodegenerative disorders such as Parkinsonism is unclear and may depend in part on the degree of recovery. Here we assessed the effects of protracted abstinence on the loss of DA transporters in striatum, in methamphetamine abusers using positron emission tomography and [11C]d-threo-methylphenidate (DA transporter radioligand). Brain DA transporters in five methamphetamine abusers evaluated during short abstinence (<6 months) and then retested during protracted abstinence (12–17 months) showed significant increases with protracted abstinence (caudate, +19%; putamen, +16%). Although performance in some of the tests for which we observed an association with DA transporters showed some improvement, this effect was not significant. The DA transporter increases with abstinence could indicate that methamphetamine-induced DA transporter loss reflects temporary adaptive changes (i.e., downregulation), that the loss reflects DA terminal damage but that terminals can recover, or that remaining viable terminals increase synaptic arborization. Because neuropsychological tests did not improve to the same extent, this suggests that the increase of the DA transporters was not sufficient for complete function recovery. These findings have treatment implications because they suggest that protracted abstinence may reverse some of methamphetamine-induced alterations in brain DA terminals.

Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies

Methylphenidate is the most commonly prescribed drug for the treatment of ADHD. We have used positron emission tomography to assess the role that methylphenidates effects in brain dopamine have on its therapeutic and reinforcing effects. We have documented that in the human brain therapeutic doses of methylphenidate block more than 50% of the dopamine transporters and significantly enhance extracellular DA, an effect that appears to be modulated by the rate of DA release. Thus, we postulate that methylphenidates therapeutic effects are in part due to amplification of DA signals, that variability in responses is in part due to differences in DA tone and that methylphenidates effects are context dependent. Methylphenidate-induced increases in DA are also associated with its reinforcing effects but only when this occurs rapidly, as with intravenous administration. Moreover, abuse of methylphenidate is constrained by its long half-life, which we postulate limits the frequency at which it can be administered.

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidates side effects may counterbalance its reinforcing effects.

Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study

Imaging studies in patients with Type II alcohol dependence have revealed significant reductions in dopamine (DA) D2 receptor availability. Here we assessed the effects of alcohol detoxification in DA D2 receptors in alcoholic subjects. We evaluated 14 patients with Type II alcohol dependence tested within 6 weeks of detoxification and then re-tested 1-4 months later while alcohol free. The comparison group comprised 11 healthy controls. PET was used with [11C]raclopride to measure DA D2 receptors. Eight alcoholics and all control subjects were tested with a CTI 931 PET scanner and six alcoholics with a Siemens HR+ PET scanner. Data were analyzed separately for the studies done in the different scanners. Comparisons between early and late alcohol detoxification showed no significant changes in DA D2 receptor availability (B(max)/K(d)) for the studies done with the CTI and the HR+ scanners. Comparison with controls showed lower DA D2 receptor levels in caudate and putamen in alcoholics tested during early detoxification and in caudate during late detoxification. These studies replicate previous findings of lower striatal DA D2 receptors in alcoholics than in controls and absence of significant recovery during alcohol detoxification. These findings suggest that low DA D2 receptor availability in alcoholics is not due to alcohol withdrawal and may reflect a predisposing factor.

Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain.

Abstract  Methylphenidate (Ritalin) is the most commonly prescribed psychoactive medication for children in the US where it is used for the treatment of attention deficit hyperactivity disorder. Methylphenidate is marketed as a racemic mixture of the d-threo and l-threo enantiomers. It is believed that the d enantiomer is responsible for the therapeutic effect of methylphenidate. In this study we labeled the individual enantiomers with carbon-11 and compared their binding and pharmacokinetics in the human and baboon brain. Microdialysis studies in the rat were performed to compare their potency in elevating striatal dopamine concentration. Positron emission tomographic (PET) studies with [11C]d-threo-methylphenidate ([11C]d-threo-MP) demonstrated highest regional uptake in basal ganglia. In contrast, [11C]l-threo-methylphenidate ([11C]l-threo-MP) displayed similar uptakes in all brain regions. The ratios of distribution volumes at the steady-state for the basal ganglia to cerebellum (DVBG/DVCB) ranged from 2.2 to 3.3 for [11C]d-threo-MP in baboon and human, and only 1.1 for [11C]l-threo-MP. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) markedly reduced the striatal but not the cerebellar uptake of [11C]d-threo-MP, whereas there was no effect on DVBG/DVCB for [11C]l-threo-MP. In the rat, d-threo-MP increased extracellular dopamine concentration by 650% whereas l-threo-MP did not affect dopamine levels. These results indicate that pharmacological specificity of MP resides entirely in the d-threo isomer and directly show that binding of the l-isomer in human brain is mostly non-specific.

Dopamine-transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans

Abstract Objectives: Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than 50% occupancy for perception of the ”high”. The present experiments were conducted to examine dose–occupancy and dose–effect relationships in mice for cocaine and also for methylphenidate, a dopamine uptake blocker used in pediatric psychiatry. Methods: Percentage occupancies of the dopamine transporter by cocaine and methylphenidate were estimated after intravenous injection in mice from the displacement of in vivo binding of [3H]cocaine from the striatum. Locomotor activity was measured in a photocell apparatus. Results: The relationship between drug doses (milligrams of hydrochloride salt per kilogram body weight) and percentage occupancy of the dopamine transporter was indistinguishable for cocaine and methylphenidate, and corresponded to about 50% occupancy at 0.25 mg/kg and about 80% at 1 mg/kg. This was similar to the relationship between drug dose and transporter occupancy, previously measured in human and baboons using [11C]cocaine or [11C]d-threo-methylphenidate and PET. Methylphenidate increased locomotor activity in the mice substantially more than cocaine at the same dose and the same degree of dopamine-transporter receptor occupancy. Conclusions: The range of dopamine-transporter occupancy required for behavioral activation in the mice was thus similar to that previously reported for experience of a cocaine- or methylphenidate-induced ”high” in human subjects. Our results are consistent with other studies in which both cocaine and methylphenidate were evaluated in animal behavioral assays and were found to have very similar psychopharmacological properties.

Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol

This study investigates the rate of age-related dopamine D2 receptor loss as determined by positron emission tomography (PET) and 11C-raclopride and compares it with D2 loss previously estimated with 18F-N-methylspiroperidol (NMS). Dopamine D2 receptors were measured with 11C-raclopride in 24 healthy volunteers (24-73 years of age) using the ratio of the distribution volume in striatum to that in cerebellum (Bmax/Kd + 1). The results were compared with those obtained in 20 healthy male volunteers (20-49 years of age) in whom D2 receptors were measured with NMS using the ratio index (slope of the striatum-to-cerebellum ratio as a function of time). Findings of correlational analysis between age and dopamine D2 receptor availability were significant for both ligands. Estimates of dopamine D2 receptor loss per decade corresponded to 7.9% for the 11C-raclopride study and 7.8% for the NMS study. Both ligands documented significant age-related decreases in dopamine D2 receptors that occurred relatively early in life (40 years of age).

Cocaine uptake is decreased in the brain of detoxified cocaine abusers

Binding of [11C]cocaine in brain was measured with positron emission tomography in 12 detoxified cocaine abusers and in 20 controls to evaluate if there were changes in cocaine binding and in dopamine (DA) transporter availability associated with chronic cocaine use. Nine controls and 10 cocaine abusers had an additional scan with [18F]N-methylspiroperidol to measure dopamine D2 receptors. Cocaine abusers had significantly lower uptake of [11C]cocaine in brain (6.2 ± 1% dose/cc tissues) than controls (7.7 ± 2%). The distribution volumes (DV) for [11C]cocaine were reduced in basal ganglia (BG), cortex, thalamus, and cerebellum (CB) of cocaine abusers. However there were no differences in the ratio of the DV in BG to that in CB, which is an estimate of DA transporter availability. Values for DA D2 receptor availability were decreased in cocaine abusers and did not correlate with estimates of dopamine transporter availability. In summary, detoxified cocaine abusers showed decreased uptake of cocaine in brain but did not show changes in DA transporter availability.

Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain.

Though the blockade of dopamine transporters (DAT) is associated with cocaines and methylphenidates reinforcing effects, it is the stimulation of dopamine (DA) receptors, achieved by increases in synaptic DA, that enables these effects to occur. Positron emission tomography (PET) and [11C]raclopride were used to assess the levels of occupancy of DA D2 receptors by dopamine achieved by doses of cocaine or methylphenidate previously documented to block over 70% of DAT. Studies were performed in five baboons using a paired scan protocol designed to measure DA D2 receptor availability (Bmax/Kd) at baseline conditions and after intravenous administration of either cocaine or methylphenidate. Cocaine (1–2 mg/kg) or methylphenidate (0.5 mg/kg) administered 5 min prior to [11C]raclopride decreased Bmax/Kd by 29 ± 3% and 32 ± 4%, respectively. Smaller reductions in Bmax/Kd (13% for cocaine given 30 min before [11C]raclopride and 25 ± 10% for methylphenidate given 40 min before [11C]raclopride) were seen with longer periods between drug and radioligand. These observations are consistent with the slower striatal clearance kinetics of [11C]methylphenidate than [11C]cocaine observed in previous PET experiments and with the approximately twofold higher potency of methylphenidate than cocaine in in vitro experiments. Though the elevation of synaptic DA induced by >70% occupancy of DAT by these drugs lead to a modest increase in occupancy of D2 receptors (25–30%), further studies are required to assess if this is an underestimation because of differences in D2 receptor binding kinetics between raclopride and DA. Synapse 31:59–66, 1999.

Temporal relationships between the pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular effects

Positron emission tomography was used to compare the pharmacokinetics of [11C]methylphenidate in the human brain with the temporal course of the subjective and cardiovascular effects observed after intravenous methylphenidate (0.5 mg/kg). Four subjects were tested twice with [11C]methylphenidate, at baseline and after methylphenidate. All subjects showed almost identical uptake of11C labeled drug in brain, as well as a very similar decrease in binding of [11C]methylphenidate in basal ganglia, after pretreatment with methylphenidate. In contrast, the magnitude of the behavioral and cardiovascular changes induced by methylphenidate varied among the subjects. The temporal course for methylphenidate effects paralleled closely the pharmacokinetics of [11C]methylphenidate in brain for the perception of “restlessness” and for changes in systolic blood pressure and heart rate. In contrast, methylphenidate induced “high”, “anxiety” and changes in diastolic blood pressure decreased rapidly despite long lasting binding of the drug in brain. These results indicate that binding of methylphenidate in brain does not appear to predict individual responses to the drug and that more than one neurotransmitter and/or adaptation process are likely to be involved in the behavioral and cardiovascular effects of methylphenidate.